Background As suicide epidemics appear resilient to current organizational and individual approaches, and as our pharmacological arsenal for suicide prevention is stagnant, there is a fundamental need to increase our understanding about the biological mechanisms underlying suicidal self-directed violence (SSDV). The goals of this proposal are therefore to investigate infectious and immune biological processes that contribute to SSDV. Infection with Toxoplasma gondii (T. gondii), markers of inflammation and elevations of kynurenines have been separately associated with SSDV. However, no studies have investigated T. gondii, inflammation, and kynurenine (KYN) interdependently, and in interaction with traits of impulsivity and aggression as well as neuropsychological deficits considered as intermediate phenotypes for SSDV. Moreover no previous study has examined these associations in higher lethality attempts by Veterans, a population at higher risk for both suicide as well as, through deployment to Middle East, T. gondii exposure. From a molecular standpoint, the project will test whether T. gondii IgG seropositivity, and high levels of proinflammatory cytokines, KYN and its neurotoxic metabolite quinolinic acid (QUIN) are associated with SSDV. Conceptually, the project will explore molecular resilience supported by our preliminary data that a high index of activity of the enzyme aminocarboxy-muconate semialdehyde decarboxylase (ACMSD) leading to the production of a neuroprotective molecule, picolinic acid (PIC) at the expense of QUIN may provide resilience to suicide elevating effects of infection and inflammation. Finally, the potentil capacity of trait aggression mediating role of aggression and decision making deficits to mediate the link between T gondii seropositivity, inflammation and SSDV will be examined. Aims The specific aims are to a) estimate associations between SSDV and T. gondii IgG seropositivity (Aim 1) and Kynurenine and its metabolite levels (Aim 2), in interaction with markers of immune activation; b) investigate associations between T. gondii and impulsivity, aggression, decision making deficits, previously described as intermediate phenotypes for SSDV (Aim 3), and c) to analyze interactions between infection, inflammation, kynurenines, intermediate phenotypes and SSDV (Integrative Aim 4). Methods We will compare T. gondii seropositivity, KYN and its metabolites QUIN and PIC, and inflammation markers in Veterans who receive mental health services with (N=300) vs. those without (N=300) history of SSDV who had at least one suicide attempt of high lethality. Veterans will be recruited on the inpatient units, outpatient mental health clinics and in the community at Baltimore, Atlanta, or Denver VAs. All participants will be carefully diagnosed, and evaluated for history of suicidal behavior and suicidal ideation, as well as factors known to interact with inflammation or SSDV. T. gondii seropositivity will be measured by enzyme-linked Immunosorbent assay, KYN with High Pressure Liquid Chromatography, KYN metabolites with Gas chromatography-mass spectrometry, impulsivity and aggression with well-validated questionnaires. Neuropsychological tests will include Iowa Gambling Test, The Immediate and Delayed Memory Test, and the Stroop Color and Word Test. Statistical methods will be based on multivariable logistic regression and linear regression methods with GEE for clustering within VA clinical sites. Direct and indirect associations among the variables, and testing the strength of the hypothesized associations will be done using structural equation modeling. Impact We expect that this study with broad inclusion criteria, and thus generalizability for Veterans and higher lethality attempters will contribute to future predictive and interventional studies to discover combinations of bio- and neuropsychological markers to improve prognosis of SSDV, and potentially identify novel intervention targets for specific subgroups of Veterans at increased risk.